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AML and Cell Therapy

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AML ALLo HSCT after Low Toxicity CDT. Didier Blaise

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AML and Cell Therapy

  1. 1. Acute Myeloid Leukemia Allo HSCT after Low Toxicity CDT A step toward individualized allogeneic immunotherapy? Didier Blaise, MD Institut Paoli Calmettes, CRCM and Aix Marseille University Marseille, France
  2. 2. What do we know about allo HSCT? 2 Koreth J, Jama, 2009 Are these data reflecting present time? – 1982 to 2006 – Median age: 35-39 years – HLA –ID siblings – CYTBI / BUCY Evidence based medicine = Not always real life
  3. 3. Donor T Cell Donor mononuclear cell Host cells Conditioning regimen Disease Endotoxin IL2 IFN G IL1 TNF@ IL1 TNF@ CDT is a major factor for Mortality
  4. 4. Reduced Toxicity Strategies and challenges • Young: Lower NRM? – Similar GVL • Older: HSCT access? – Acceptable NRM – Efficient GVL
  5. 5. The less intensive, the less toxic? Flu-Bu-ATG N=69 Flu-TBI N=70 Age 54 (21-65) 52 (34-65) - AML/HMY - HLY 37% 63% 27% 73% - Advanced 63% 65% Blaise, D , cancer 2012 Flu-Bu- ATG Flu-TBI NRM 38% 22% Relapse 27% 54% 5 HLA-Matched, Related Allo PBSCT
  6. 6. The less intensive, the less toxic? Flu-Bu-ATG N=69 Flu-TBI N=70 Age 54 (21-65) 52 (34-65) - AML/HMY - HLY 37% 63% 27% 73% - Advanced 63% 65% Blaise, D , cancer 2012 Flu-Bu- ATG Flu-TBI NRM 38% 22% Relapse 27% 54% 2-4 aGVHD 47% 28% Ext cGVHD 61% 46% 6 HLA-Matched, Related Allo PBSCT
  7. 7. GVHD remains a major cause of death after RIC NonRelapseMortality 7 p=0.003 17% 31% 41% 12% Saillard C, Leuk & Lymphoma, 2014
  8. 8. Dose Intensity and Toxicity • DI is not the only cause of toxicity
  9. 9. The increase from 2.5 to 5 mg/kg of r-ATG dose in RIC is beneficial Devillier, R , BMT 2012 9
  10. 10. Study NMAC1 N 274 Age 60 (5-74) AML 100% CR1 / CR>1 /adv 58% / 36% / 6% CDT TBI2 BU2 BU4 100% R-ATG 0% MRD / UD 43% / 57% 10 Feasibility of Dose Intensity in older pts 1. Gyurkockza B, J Clin Oncol 2010
  11. 11. Study NMAC1 RIC2 MA-LTC3 N 274 102 79 Age 60 (5-74) 58 (20-70) 58 (55-76) AML 100% 100% 80% CR1 / CR>1 /adv 58% / 36% / 6% 76% /20% / 4% 32% / 23% / 47% CDT TBI2 BU2 BU4 100% 100% 100% R-ATG 0% 100% 1 AG mm / UD MRD / UD 43% / 57% 56% / 44% 52% / 48% 11 Feasibility of Dose Intensity in older pts 1. Gyurkockza B, J Clin Oncol 2010 2. Oudin C, haematologica 2014 3. Alatrash G, BBMT 2011
  12. 12. Study NMAC1 RIC2 MA-LTC3 N 274 102 79 Graft Failure 12 0 0 100 days NRM 4% 5% 5% Overall NRM 26% 24% 26% 12 Feasibility of Dose Intensity in older pts 1. Gyurkockza B, J Clin Oncol 2010 2. Oudin C, haematologica 2014 3. Alatrash G, BBMT 2011
  13. 13. Dose Intensity and Toxicity • DI is not the only cause of toxicity • DI is not always associated with toxicity
  14. 14. CR1 AML NMAC N=160 RIC N=78 MA-RTC N= 25 14 Importance of Dose Intensity in Disease Control?
  15. 15. The less intensive, the less toxic? Flu-Bu-ATG N=69 Flu-TBI N=70 Age 54 (21-65) 52 (34-65) - AML/HMY - HLY 37% 63% 27% 73% - Advanced 63% 65% Blaise, D , cancer 2012 Flu-Bu- ATG Flu-TBI NRM 38% 22% Relapse 27% 54% 2-4 aGVHD 47% 28% Ext cGVHD 61% 46% 15 HLA-Matched, Related Allo PBSCT
  16. 16. Dose Intensity and Toxicity • DI is not the only cause of toxicity • DI is not always associated with toxicity • DI may contribute controlling disease
  17. 17. 17 • Eligibility • Poor prognosis AML/MDS • HLA identical RD or UD • Primary endpoint : 2 year PFS • Sample size: 177 patients • Quality of life study • Economics • Non interventional PK • BX Pharmacogenomics Dose Intensity study NCT: 01985061
  18. 18. Conclusions • Toxicity was (is) a major issue – Low post-transplant toxicity is achievable • It is critical for some populations: Older/unfit patients • CDT is an important adjustment variable – Low toxicity does not mean only reduced intensity • Disease control is the major issue – Low toxicity is not NO toxicity • Still some work to do... – Intensive CDT with low toxicity is achievable • Individualized CDT may be critical for better disease control – Optimized CDT may not be sufficient to cure some diseases • Post transplant therapy?
  19. 19. Why are individualized trt needed? Patel JP, NEJM, 2012 • Cytogenetics • Molecular Biology • Disease Status • MRD(?) • Age • Comorbidities Not AML… but AMLs!
  20. 20. Risk changes with accurate assessment Intermediate Risk? Patel JP, NEJM, 2012
  21. 21. Risk changes with accurate assessment E Jourdan, Blood, 2013 21 MRD CBF AML Good Risk?
  22. 22. 5-year relative survival rates with respect to age in patients with AML1 5-yearsurvivalrate 0 10 20 30 40 50 60 Age, years <45 45–54 65+55–64 1. Howlader N, et al (eds). SEER Cancer Statistics Review, 2010 2. Appelbaum FR et al, Hematology Am Soc Hematol Educ,2001 OS in patients aged >55 years (ECOG data from 1973–1997)2 Outcome of AML in the elderly
  23. 23. Older patients with CBF AML  5-years LFS: 26% CR rate: 88% Prebet et al JCO 2010
  24. 24. Not AML… but AMLs… and different patients…
  25. 25. Patient -3 -2 -1-4-6 -5 0 Immunotherapy: Allo HSCT + recent developments 25 Disease High Risk Allo-HSCT Bridge to Allo Disease High Risk Refractory • MoABs ? Bi-specifics • Car-T cells? • Checkpoint inhibitors?
  26. 26. DonorIndividualized Conditioning Patient Age Comorbidities -3 -2 -1-4-6 -5 0 26 GVHD prophylaxis Disease Stage Prognostic Factors MRD Allo-HSCT HLA match vs Alternative D NMAC/RIC vs. MA-RTC No Post-Graft IS Long vs. short term In-vivo T-cell deplet Bridge to Allo Immunotherapy: Allo HSCT + recent developments
  27. 27. DonorIndividualized Conditioning Patient Age Comorbidities -3 -2 -1-4-6 -5 0 27 GVHD prophylaxis Allo-HSCT Chimerism Disease Stage Prognostic Factors MRD Relapse Immunotherapy: Allo HSCT + recent developments Bridge to Allo
  28. 28. Donor Conditioning Patient Age Comorbidities -3 -2 -1-4-6 -5 0 28 GVHD prophylaxis Allo-HSCT Chimerism MRD Disease Stage Prognostic Factors MRD Immunotherapy: Allo HSCT + recent developments Bridge to Allo Individualized Conditioning
  29. 29. Donor Conditioning Patient Age Comorbidities -3 -2 -1-4-6 -5 0 29 GVHD prophylaxis Chimerism Individualized Immunotherapy • Cellular therapy: DLI, NK-DLI , Treg • Tumor Antigen vaccination: WT1… • Post graft drugs: Aza, Lenalidomide, anti-Kir moab… • Car? Checkpoint inhibitors? MRD Allo-HSCT Disease Stage Prognostic Factors MRD Immunotherapy: Allo HSCT + recent developments Bridge to Allo Individualized Conditioning
  30. 30. Tomorrow allogeneic immunotherapy? Immunotherapy bridge CDT MAC/MA-RTC vs. RIC Donor HLA id vs. alternative GVHD Prophylaxis No ATG vs. ATG short vs. long term CSA Post Graft immunotherapy No vs. Yes 31
  31. 31. SR CR1 Immunotherapy bridge CDT MAC/MA-RTC vs. RIC +++ Donor HLA id vs. alternative + GVHD Prophylaxis No ATG vs. ATG short vs. long term CSA ++++ Post Graft immunotherapy No vs. Yes + 32 Tomorrow allogeneic immunotherapy?
  32. 32. Tomorrow allogeneic immunotherapy? SR CR1 HR CR1 Advanced Immunotherapy bridge + +++ CDT MAC/MA-RTC vs. RIC +++ ++ + Donor HLA id vs. alternative + +++ ++++ GVHD Prophylaxis No ATG vs. ATG short vs. long term CSA ++++ ++ + Post Graft immunotherapy No vs. Yes + +++ ++++ 33
  33. 33. Conclusions • Allogeneic Immunotherapy is an effective therapy for AL • What is essential ? – Not what has been done so far… –But what we yet have to do! 34 Ollie, So much to do… Keep going! Stan
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